tbuckley/cabot-search huggingface dataset:
Prognosis of patients with resected stage II colon cancer -T4 versus T3 with two or more high-risk factors: A retrospective single-center cohort study.
Authors: Mikhail Fedyanin, Anastasia Rice, Elizaveta Polyanskaya, Sergey Gordeev, Zaman Mammadli, Sergei Tjulandin, Alexey Tryakin
Journal: Journal of Clinical Oncology (2022)

e15608 Background: in 2021 ASCO has updated guidelines on adjuvant therapy for stage II colon cancer with the statement: “Patients with T4 tumors are at higher risk of recurrence and should be offered adjuvant chemotherapy, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphatic invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT”. We performed a single-center retrospective study to assess the prognostic role of postoperative tumor stage T4 and T3 with ≥2 negative prognostic factors in patients with resected stage II colon cancer. Methods: We retrospectively analyzed 1457 pts with stage I-III colon cancer treated in Russian Cancer Research Center n.a. N.N. Blokhin from 2001 to 2015. We included pts with resected stage II colon cancer with following negative prognostic factors: T4; sampling of fewer than 12 lymph nodes in the surgical specimen; perineural or lymphatic invasion; poorly or undifferentiated tumor grade; intestinal obstruction; and tumor perforation. Three cohorts were studied: pts with pT4N0M0 with no other high-risk factors (group A), pts with pT4N0M0 with additional high-risk factors (group B), and pts with pT3N0M0 with ≥2 high-risk factors (group C). The primary study endpoint was 3-year disease-free survival (DFS). The secondary endpoint was 5-year overall survival (OS). Statistical analysis was done with SPSS v.20. Results: 164 pts met the inclusion criteria with 17 (10%) pts in group A, 90 (55%) pts in group B, and 57 (35%) pts in group C. Adjuvant chemotherapy was performed in 8 (47%), 25 (28%), and 9 (16%) pts, respectively (p = 0.035). At a median follow-up of 62 months (range, 2-135 months), the 3-year DFS was 82%, 68%, and 78% for groups A, B, and C, respectively (HR, 1.55; 95% CI, 0.99-2.4; p = 0.053). No difference in 3-year DFS was found between group A and C (HR, 1.0; 95% CI, 0.34-3.2; p = 0.9). The 5-year OS was 75%, 65%, and 78% for groups A, B, and C, respectively (HR, 1.38; 95% CI, 0.84-2.3; p = 0.2). Conclusions: Patients with pT4 with additional high-risk features had worse overall survival compared to other subgroups with resected stage II colon cancer. There was no difference in survival rates between patients with pT4 with no additional negative prognostic factors and pT3 with ≥2 negative prognostic factors. Therefore, we propose that patients with pT4 as well as with pT3 with ≥2 negative prognostic factors are at a higher risk of recurrence and should be offered adjuvant chemotherapy.
Actual immune checkpoint inhibitor drug use in U.S. patients with cancer.
Authors: Alia Rawji, Henry J. Henk, Stacey DaCosta Byfield, Jennifer Malin
Journal: Journal of Clinical Oncology (2022)

2608 Background: By 2018, seven Immune Checkpoint Inhibitor (ICI) drugs had gained FDA approval in nine cancers and the number of indications has continued to increase. Haslam et al. estimated that between 36.1 and 38.5% of US patients with cancer were eligible for ICI therapy in 2019. We report the use of ICI dugs in the first-line of therapy (LOT1) and second-line (LOT2) among enrollees treated for 9 cancers with an FDA indication approval in or before 2017. Methods: A cohort of patients treated for one of the nine most common cancers with an FDA indication for ICI drugs in 2017 was identified using de-identified data from the OptumLabs Data Warehouse, and clinical information from the Optum Cancer Guidance Program’s electronic prior authorization (ePA) platform. De-identified administrative claims data were then linked to ePA information (cancer type &amp; diagnosis date) at the patient level to identify details of treatment received. Eligible patients were enrolled in a commercial or Medicare Advantage (MA) plan and initiated treatment within six months of diagnosis, enrolled at least six months prior to diagnosis date (ensuring this was the LOT1) and at least thirty days after start of first identified treatment regimen (to identify the full treatment regimen). LOT1 treatment initiation ranged from 1/1/2017 to 12/31/2020 for those who were diagnosed before 6/30/2020. ICI regimens are defined as those with an ICI drug received within first thirty days of the LOT start date. Results: In this population, we identified 17,283 eligible patients treated for non-small cell lung cancer (4654), melanoma (705), renal cell carcinoma (554), bladder cancer (1974), colorectal (4502), hepatocellular carcinoma (673), gastric cancer (1786), head and neck cancer (1923), or Hodgkin lymphoma (512) in 2018, 2019, and 2020. Overall, 3,291 (19%) of these patients received an ICI in LOT1 with rates increasing over time. The highest rates of ICI use in LOT1 are for the treatment of melanoma, remaining consistent over time, while ICI use in LOT2 is highest for the treatment of non-small cell lung cancer although evidence from 2020 suggests this may be waning. Among patients being treated for renal cell carcinoma, ICI use in LOT2 decreased from 43% (2018) to 15% (2020) while LOT1 ICI use increased to 81% in 2020. Conclusions: Overall, ICI use has changed over time in both the first- and second-line setting. In particular, we observe a shift in ICI use from LOT2 to LOT1, consistent with the more recent FDA approvals in earlier lines of therapy.[Table: see text]
Efficacy and safety of relugolix in men with advanced prostate cancer based on baseline body mass index (BMI): A subgroup analysis from the randomized, phase 3 HERO study versus leuprolide (LEU).
Authors: Fred Saad, Daniel J. George, Michael Cookson, Daniel Saltzstein, Ronald F. Tutrone, Marc B. Garnick, Bruce Brown, Sophia Lu, Mark Fallick, Sarah Hanson, E. David Crawford, Neal D. Shore
Journal: Journal of Clinical Oncology (2022)

5073 Background: BMI has been correlated with adverse prostate cancer outcomes, such as risk of biochemical failure, mortality and androgen deprivation therapy complications. Relugolix is a FDA-approved, once-daily oral GnRH receptor antagonist that has demonstrated superior continuous suppression of testosterone (T) to castrate levels through Week 48 compared to LEU (96.7% vs 88.8%, respectively; Shore N, NEJM 2020;382:2187) in men with advanced prostate cancer (APC). This HERO subgroup analysis looks at the impact of baseline BMI on efficacy and safety. Methods: HERO was a phase 3 randomized, open-label study to evaluate relugolix vs LEU in 930 men with APC. This analysis looked at all men enrolled and treated in the HERO study divided by baseline BMI (BMI subgroups: &lt;25.0 [underweight and healthy weight]; 25.0 – 29.9 [overweight]; and &gt;29.9 [obese]). Assessments included sustained T suppression to castrate levels (&lt;50 ng/dL) from Day 29 through 48 weeks, early T suppression to castrate levels (Day 4 and Day 15), prostate specific antigen (PSA) response (&gt;50% decrease from baseline) at Day 15 with confirmation at Day 29, and profound castration rate (&lt;20 ng/dL) at Day 15. T recovery subset analysis was not included due to low patient numbers. All analyses performed were descriptive. Results: Of the 930 men (relugolix:622; LEU:308) treated in HERO, 287 (30.9%) men had BMI &lt;25, 424 (45.6%) were 25 – 29.9, 219 (23.5%) were &gt;29.9. Sustained castration rates through 48 weeks were higher for the relugolix group than the LEU group and results for select key secondary endpoints were generally consistent across BMI categories, although PSA response proportions were lower in obese patients (table). No differences were noted in the incidence or types of adverse events within treatment groups in the subgroups analyzed. Conclusions: In this HERO study subgroup analysis, relugolix demonstrated greater continuous T suppression than LEU regardless of baseline BMI. Although higher BMI has been associated with poorer outcomes, we did not observe a similar trend with T responses. A numerically lower PSA response was seen in obese patients. Additional research with longer follow-up is warranted. Clinical trial information: NCT03085095. [Table: see text]
Systematic genomics-based approach for developing new therapeutics and diagnostics for esophageal cancer.
Authors: Yataro Daigo, Atsushi Takano, Yusuke Nakamura
Journal: Journal of Clinical Oncology (2022)

e16034 Background: As the prognosis of advanced esophageal cancer patients is still poor after standard therapies, development of new molecular therapies with minimum risk of adverse events and cancer biomarkers for companion diagnostics is eagerly awaited. Methods: We have been screening new therapeutic target molecules and biomarkers for esophageal cancers as follows; i) To identify highly expressed genes in esophageal cancers by gene expression microarray analysis, ii) To verify the target molecules for their low expression in normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 265 esophageal cancers, and iv) To confirm their function for the growth and/or invasive ability of esophageal cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate oncoproteins and selected ESOC1 (esophageal cancer-associated oncoprotein 1) that has a methyltransferase domain. We first confirmed its in vitro methyltransferase activity. Immunohistochemical analysis showed that ESOC1 positivity was detected in 68.5% of esophageal cancers and associated with tumor size. Moreover ESOC1 positivity was an independent prognostic factor for patients with esophageal cancer. Knockdown of ESOC1 expression by siRNAs suppressed growth of esophageal cancer cells. Exogenous expression of ESOC1 increased the growth of mammalian cells. Therefore, ESOC1 is likely to be a prognostic biomarker and therapeutic target for esophageal cancers. Conclusions: Systematic genomics-based approach could be useful for the selection of novel candidate cancer biomarkers and therapeutic targets for small molecules, antibodies, nucleic acid drugs, and immunotherapies.
The landscape of <i>EGFR</i> mutation in Chinese patients with glioma.
Authors: Hui Zhang, Rongjie Tao, Xiaofeng Zhu, Ningning Luo, Yingxue Qi, Mengmeng Li, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e14028 Background: Epidermal growth factor receptor (EGFR), a trans-membrane receptor tyrosine kinase, consists of an extracellular ligand-binding domain (ECD), a single transmembrane domain (STMD) and an intracellular kinase domain (ICD). Glioma is the most common primary brain tumor, and variations of EGFR are frequently reported in glioma patients. This study aimed to analysis the landscape of EGFR mutation subtype in Chinese patients with glioma. Methods: We retrospectively collected 1779 patients with glioma. In all patients enrolled, the comprehensive genomic profiling containing EGFR gene was detected using tumor tissue, including WES, 539 tumor related-gene panel or 131+4 gene panel (Simceredx). And the somatic mutations including SNV, INDEL, CNV, fusion were analyzed correspondingly. Results: Among 1779 patients with glioma, EGFR mutations were identified in 392 (22.03%) patients. The age was significantly higher in patients with EGFR-mutant group than in patients without EGFR-mutant group, with median age 54 vs. 45 (p = 4.81e-19). The sex didn’t reach statistical significance in two group. The incidence rate of different EGFR mutation types among all patients with EGFR-mutant were amplification (314,80.10%), SNV(198,50.51%), Indel(24,6.12%) and fusion(44,11.22%) respectively. 162 (46.69%) had two or more mutation types simultaneously. The main partner gene of EGFR fusion was LOC100996654, followed by ELDR and SEC61G, and the main EGFR breakpoints were in intron24, intron7, exon7. Within 347 SNV and Indel mutations, exon7, 15, 20, 6 and 8 were detected in 103(29.68%), 50(14.41%), 28 (8.07%), 25(7.20%) and 18 (5.19%) respectively. The top three mutaton subtypes within exon7 were account for 19.31%, which included p.A289V,p.A289T,p.T263P. Meanwhile, the mutation frequency within ICD encoded by exons 18-24 was 17.00%, in which exon20 mostly distributed (8%). In exon20, the most common mutation subtypes were p.V774M,p.H773dup,p.T790M, while in the second proportion exon18 (3.46%), the main subtype were p.G719A/D. Conclusions: EGFR amplification was the most common mutation type. There were 122 SNV and Indel subtypes altogether and occurred throughout almost the entire exon region, in which exon7 contained maximum 21 different subtypes and the p.A289V was the main type. The distribution of subtypes in ECD were much more than in ICD. The relationship between subtypes occurrence and cancer will be further studied in the future.
Pan-cancer analysis of <i>PBRM1</i> mutation and their association with immune-related biomarkers and prognosis.
Authors: Xujun He, Yaqun Xin, Hongling Yuan, Houquan Tao, Qingqing Wang, Honglin Zhu
Journal: Journal of Clinical Oncology (2022)

e14536 Background: Polybromo 1 ( PBRM1), which is required for the stability of the SWI/SNF chromatin remodeling complex, is often deleted or mutated in clear cell renal cell carcinoma (ccRCC). However, the prognostic value of PBRM1 in ccRCC with immunotherapy was controversial and less explored in other cancer types. Methods: The sequencing data and clinical information of patients were obtained from The Cancer Genome Atlas (TCGA) cohort (n = 10967) and the immunotherapy MSKCC cohort (n = 387). In TCGA cohort, the expression levels of PD1 were defined as high or low using a 75% cut-off. The association of PBRM1 mutation and related immune biomarkers such as PD1, TMB and immune infiltrates CD4+ and CD8+ T cells was analyzed. Results: Loss-of-function (LOF) of PBRM1 mutation ( PBRM1 LOF ), including frameshift, nonsense and splice, accounted for 61.4% of all somatic mutations, with a frequency of 2.2% across all cancer types. It is most common in renal clear cell carcinoma (KIRC; 23.2%, 119/512), followed by stomach adenocarcinoma (STAD; 4.1%, 18/440), uterine corpus endometrial carcinoma (UCEC; 3.8%, 20/529), and colon adenocarcinoma (COAD; 2.5%, 11/439) in TCGA cohort. In KIRC, no differences of PD1 expression (P = 0.307) and TMB (P = 0.389) were observed between patients with PBRM1 LOF and non- PBRM1 LOF mutations, while in STAD, UCEC and COAD, patients with PBRM1 LOF mutations had significantly higher levels of PD1 (P = 0.002 in COAD, P &lt; 0.001 in STAD and UCEC) and TMB (all P &lt; 0.001). As for immune infiltrates, expression levels of CD4+ (P = 0.34) and CD8+ (P = 0.18) were found no difference between patients with PBRM1 LOF and non- PBRM1 LOF in KIRC. However, significantly higher expression levels of CD4+ (P = 0.0014) and CD8+ (P = 0.0016) in UCEC, and CD8+ in COAD (P = 0.04) were found in patients with PBRM1 LOF compared with non- PBRM1 LOF mutations. Further, in MSKCC cohort, a cohort of patients who had undergone immunotherapy, PBRM1 LOF was shown no significant effect on patient outcome in KIRC (P = 0.42), while in other cancer types (COAD+STAD), PBRM1 LOF trended towards a promising biomarker for better survival even though the difference was not statistically significant in this small cohort (P = 0.51). Conclusions: PBRM1 LOF may play different prognostic roles on immunotherapy in different cancer types. In KIRC, PBRM1 LOF was not associated with immune-related biomarkers as well as prognosis of immunotherapy. In COAD, STAD and UCEC, PBRM1 LOF was positively associated with immune-related biomarkers and might be a promising biomarker for immunotherapy. This result needs further validation in a lager cohort.
A phase 1b/2 study of nanatinostat and valganciclovir in patients with advanced Epstein-Barr virus positive (EBV<sup>+</sup>) solid tumors and in combination with pembrolizumab in patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC).
Authors: A. Dimitrios Colevas, Lillian L. Siu, Darren Wan-Teck Lim, Bo Gao, Lisa Rojkjaer, Afton Katkov, Yisrael Katz, Brigette Ma
Journal: Journal of Clinical Oncology (2022)

TPS6107 Background: Epstein-Barr virus (EBV) is linked to the development and pathogenesis of nasopharyngeal carcinoma (NPC). Most patients present with advanced stage disease at diagnosis (Li 2014); first-line chemoradiation is commonly followed by recurrence and poor prognosis emphasizing the need for new treatment options. Targeting EBV in NPC represents a novel therapeutic approach. EBV is predominantly latent in NPC; pre-clinical studies demonstrated that induction of the viral lytic phase by histone deacetylase inhibitors (HDACi) renders EBV + tumor cells susceptible to the cytotoxic activity of ganciclovir (GCV) (Hui 2016). Nanatinostat (Nstat), a potent Class-I HDACi, induces the expression of the lytic BGLF4 protein kinase in EBV + tumor cells, which activates the nucleoside analog GCV via phosphorylation. Phosphorylated GCV becomes incorporated into the cellular DNA causing chain termination and apoptosis. The all-oral combination of Nstat and valganciclovir (VGCV), a pro-drug of GCV, has demonstrated favorable safety and preliminary efficacy in a phase 1/2 study in patients with recurrent EBV + lymphoma (NCT03397706). This phase 1b/2, open-label, multicenter study will evaluate the safety, tolerability, pharmacokinetics, and preliminary activity of Nstat + VGCV in patients with advanced EBV + solid tumors. Additionally, the combination of pembrolizumab together with Nstat + VGCV will be evaluated in recurrent/metastatic NPC (RM-NPC) patients. NPC frequently exhibits high PD-L1 expression levels; however, PD-1 inhibitors resulted in limited response rates ranging from 20-30% in the RM-NPC setting. Methods: Phase 1b utilizes a 3+3 dose escalation design to determine the recommended Phase 2 dose (RP2D) of Nstat + VGCV in patients with EBV + RM-NPC. In Phase 2, up to 60 patients with EBV + RM-NPC will be randomized 1:1 to receive Nstat + VGCV at the RP2D with or without pembrolizumab to evaluate safety, tolerability, overall response rate, and potential pharmacodynamic markers of drug activity, including plasma EBV DNA levels. Additionally, patients with EBV + solid tumors other than RM-NPC will receive Nstat + VGCV at the RP2D in a separate Phase 1b dose expansion cohort. Patients eligible for the phase 1b dose escalation and phase 2 will have EBV + RM-NPC with 1-3 prior lines of platinum-based chemotherapy and no available curative therapies. Patients with advanced EBV + non-NPC solid tumors (gastric cancer, lymphoepithelioma-like carcinoma, leiomyosarcoma) and no curative therapies are eligible for the phase 1b expansion cohort. All patients must have measurable disease per RECIST v1.1 and adequate bone marrow, liver, and renal function. Enrollment began in January 2022. Clinical trial information: NCT05166577.
Responses to the MET inhibitor tepotinib in gastric cancers with MET amplification or both high PD-L1 expression and an MET exon 14 skipping mutation.
Authors: Dae Young Zang, Sung-Hwa Sohn, Hee Jung Sul, Bum Jun Kim, Hyeong Su Kim
Journal: Journal of Clinical Oncology (2022)

e16037 Background: Aberrant expression of MET involving MET exon 14 (METex14) alteration and high CNV, which leads to enhanced tumorigenesis. In addition, the PD-L1 (CD274) is often upregulated in cancers. This study characterized expressions of MET (including METex14 skipping mutation), PD-L1 and CD44 in human gastric cancer (GC) cell lines, and further characterized the differential susceptibility of these cell lines to tepotinib. Methods: We assessed the antitumor activity of tepotinib in GC cell lines. CNV analysis using targeted next-generation sequencing (NGS) techniques. The effect of tepotinib on cell viability (IC 50 ), apoptotic cell death, migration, the PD-L1, CD44 and c-MET signaling were evaluated by MTS assay, flow cytometry, wound-healing assay, western blotting, and qRT-PCR. Results: Tepotinib treatment showed dose-dependent growth inhibition of c-MET-amplified SNU620, MKN45, Hs746T, SNU638 and KATO III cells with concomitant induction of apoptosis. Tepotinib treatment also significantly reduced expressions of phospho-c-MET, total c-MET, VEGFR2, Snail and c-Myc protein in SNU620, MKN45 and Hs746T cells. Especially, tepotinib significantly reduced the expressions of CD44 and PD-L1 in METex14 skipping mutated Hs746T cells. In contrast, this drug was only slightly active against KATO III and SNU638 cells. Migrations were more reduced in the tepotinib-treated group than in the control group. Conclusions: These data show the possibility that tepotinib may have therapeutic effects in c-MET-amplified GC and both high PD-L1 expression and an MET exon 14 skipping mutation, suggesting that clinical studies need to confirm the therapeutic effect.
Defining more precisely the effects of docetaxel plus ADT for men with mHSPC: Meta-analysis of individual participant data from randomized trials.
Authors: Claire Louise Vale, David Fisher, Peter Godolphin, Larysa H Rydzewska, Jean-Marie Boher, Sarah Burdett, Yu-Hui Chen, Gwenaelle Gravis, Nicholas D. James, Glenn Liu, Laura Murphy, Mahesh K. B. Parmar, Ewelina Rogozinska, Patrick Sfumato, Christopher Sweeney, Matthew R. Sydes, Bertrand F. Tombal, Ian R White, Jayne F. Tierney
Journal: Journal of Clinical Oncology (2022)

5070 Background: Adding docetaxel to androgen deprivation therapy(ADT) improves survival in metastatic, hormone-sensitive prostate cancer (mHSPC), but uncertainty remains about who benefits most. To investigate this thoroughly and reliably, the STOPCAP M1 collaborationconducted a meta-analysis of individual participant data (IPD) from relevant trials. Methods: Methods were included in a registered protocol ( CRD42019140591 ). Updated IPD from the GETUG-15, CHAARTED and STAMPEDE trials were harmonised and checked. The main outcomes were overall survival (OS), progression-free survival (PFS) and failure-free survival (FFS). Overall pooled effects were estimated using intention-to-treat, 2-stage, fixed-effect meta-analysis, adjusted for age, PSA, Gleason sum score, performance status, and timing of metastatic disease (missing covariate values imputed), with 1-stage and random-effects sensitivity analyses. We assessed subgroup effects using 2-stage, fixed-effect meta-analysis of within-trial interactions, adjusted for the same covariates. We based these on PFS to maximise power, and OS whenever interactions were found. To explore multiple subgroup interactions, and to derive subgroup-specific absolute treatment effects, we used 1-stage, flexible parametric modelling and standardisation. Results: We obtained IPD for all 2261 men randomised, with median FU of 6 years (all patients). There were clear relative benefits of docetaxel on OS (HR = 0.79, 95% CI 0.70 to 0.88, p&lt;0.0001), PFS (HR = 0.70, 95% CI 0.63 to 0.77, p&lt;0.0001) and FFS (HR = 0.64, 95% CI 0.58 to 0.71, p&lt;0.0001). With evidence of non-proportional hazards, we also estimated 5-year absolute differences: OS 10% (95% CI 6 to 15%), PFS 9% (95% CI 5 to 13%) and FFS 9% (95% CI 6 to 12%). The relative effect of docetaxel on PFS differed by volume of metastases (interaction p=0.027; high volume HR = 0.60, 95% CI 0.52 to 0.68; low volume HR = 0.78, 95% CI 0.64 to 0.94), and timing of metastatic disease (interaction p=0.077; synchronous HR = 0.67, 95% CI 0.60 to 0.75; metachronous HR = 0.89, 95% CI 0.67 to 1.18). OS results were similar. When metastatic disease volume and timing were combined, docetaxel appeared to improve PFS and OS for all men, except those with low volume, metachronous disease (Table). Conclusions: This IPD meta-analysis provides the most detailed assessment of the effects of docetaxel for mHSPC, and suggests that men with low volume, metachronous disease should be managed differently to those with other types of metastatic disease. [Table: see text]